Euthyroid hyperthyroxinemia and hypothyroxinemia

INTRODUCTION — 

Many conditions result in increases or decreases in serum total thyroxine (T4) and triiodothyronine (T3) concentrations, associated with normal thyroid-stimulating hormone (TSH) concentrations and no symptoms or signs of thyroid dysfunction. This constellation of laboratory values has been referred to as euthyroid hyperthyroxinemia and hypothyroxinemia, respectively. In this scenario, the serum free T4 should be normal, but many assays will report slightly abnormal values; for example, the free T4 index and many direct free T4 assays report high values in familial dysalbuminemic hyperthyroxinemia (FDH).

The detection of a normal serum TSH concentration associated with a high or low serum T4 concentration, and sometimes free T4 concentration, should immediately alert the clinician to search for one of the causes of euthyroid hyper- or hypothyroxinemia, especially if the patient has no symptoms or signs of either hyper- or hypothyroidism. Recognition of euthyroid hyper- or hypothyroxinemia is important to prevent unnecessary treatment of patients.

This topic will review these conditions. Individual thyroid function tests are discussed in detail separately. (See "Laboratory assessment of thyroid function".)

DEFINITIONS

●Euthyroid hyperthyroxinemia – Euthyroid hyperthyroxinemia is characterized by increases in serum total T4 concentrations, normal TSH concentrations, and no symptoms or signs of thyroid dysfunction.

●Euthyroid hypothyroxinemia – Euthyroid hypothyroxinemia is characterized by decreases in serum total T4 concentrations, normal TSH concentrations, and no symptoms or signs of thyroid dysfunction.

Depending upon the etiology, T3 concentrations may be increased, reduced, or normal.

In the past, these conditions presented a diagnostic challenge, and many patients were inappropriately treated for thyroid disease. However, since most clinicians measure serum TSH as a screening test for thyroid function, and most laboratories now use automated "direct" free T4 assays when needed, a normal serum TSH value is usually not followed by measurement of a total serum T4. Therefore, euthyroid hyperthyroxinemia and hypothyroxinemia frequently remain undetected, with no harm to the patient.

EUTHYROID HYPERTHYROXINEMIA

Diagnosis — Euthyroid hyperthyroxinemia is a biochemical diagnosis. It should be suspected in patients with a normal TSH, an elevated serum total T4, and no signs or symptoms of thyroid dysfunction.

If not previously obtained, measure free T4.

●If the free T4 is normal, the diagnosis is confirmed. There is no need to measure any other thyroid tests and no need for treatment.

●If the free T4 is elevated, measure either of the following:

•Free T4 by equilibrium dialysis/tandem mass spectrometry (LC-MS/MS). If normal, the patient is most likely euthyroid.

•T3 uptake with calculated free T4 index (if laboratory testing is available). If normal, the patient is most likely euthyroid. This older method of assessing free T4 was designed primarily to detect thyroxine-binding globulin (TBG) excess, one of the more common causes of euthyroid hyperthyroxinemia. (See 'TBG excess' below.)

In confusing cases, measure TBG directly, or obtain a thyroxine binding panel, which measures serum albumin, TBG, and transthyretin concentrations as well as T4 binding to each protein.

In theory, free T4 immunoassays should not be affected by changes in TBG, transthyretin, or albumin. In practice, however, many automated free T4 assays perform poorly, especially in pregnancy and nonthyroidal illness, because they are adversely affected by the lower levels of albumin and higher levels of TBG. In the second and especially the third trimester of pregnancy, automated free T4 assays frequently give low values, and some kit manufacturers attempt to compensate for the poor performance of their assay by offering adjusted lower normal ranges during the second and third trimester [1]. (See "Overview of thyroid disease and pregnancy", section on 'Thyroid adaptation during normal pregnancy' and "Overview of thyroid disease and pregnancy", section on 'Trimester-specific reference ranges' and "Thyroid function in nonthyroidal illness", section on 'Changes in thyroid hormone tests'.)

Determining the etiology — Several conditions can cause euthyroid hyperthyroxinemia (table 1). The cause may be obvious from the patient's history (particularly medications and family history).

Appropriate treatment of primary hypothyroidism — Appropriate levothyroxine replacement therapy (with normalization of serum TSH concentrations) results in serum total T4 concentrations that are 1 to 2 mcg/dL (13 to 26 nmol/L) higher than in normal subjects [2,3].

Assay artifact: Biotin — Many competitive binding assays for T4 or free T4 utilize biotinylated antibodies and a streptavidin-biotin separation technique. Excess ingestion of biotin (eg, 5000 to 10,000 mcg daily) competes with the biotinylated analog and results in spuriously high total T4 or free T4 (or total T3 or free T3) values. Measurements should be repeated after ingestion of biotin is omitted for two days [4]. Typical levels of biotin found in multivitamins, 30 to 300 mcg daily, do not interfere with these assays. (See "Laboratory assessment of thyroid function", section on 'Assay interference with biotin ingestion'.)

Binding protein abnormalities — Both T4 and T3 circulate in blood bound to one of three binding proteins:

●TBG

●Transthyretin (TTR; thyroxine-binding prealbumin [TBPA])

●Albumin

Approximately 99.97 percent of circulating T4 and 99.7 percent of circulating T3 are bound to these proteins. T4 binding is distributed as follows: TBG 75 percent, TTR 15 percent, and albumin 10 percent. In comparison, T3 is less avidly bound to TBG and TTR.

Serum total T4 or T3 assays measure both bound and free (unbound) hormone. As a result, factors that alter binding protein concentrations can have profound effects on serum total T4 (and T3) concentrations. Serum free T4 (and T3) concentrations should not change, and the patient is euthyroid. (See "Laboratory assessment of thyroid function", section on 'Serum free T4 and T3'.)

TBG excess — Thyroxine-binding globulin (TBG) excess is the most common binding protein abnormality. Patients with euthyroid hyperthyroxinemia due to TBG excess have normal TSH, high total T4, and normal free T4 index. Free T4 should also be normal, but the results are assay dependent.

●Major causes – There are several major causes of this disorder:

•Hereditary – Hereditary TBG excess is an X-linked dominant disorder characterized by TBG gene amplification and increased synthesis of TBG [5-7].

•Estrogens – Estrogens increase the glycosylation of TBG, which slows its clearance, thereby increasing serum TBG concentrations [8]. Thus, serum TBG (and total T4 and T3) concentrations are increased substantially (25 to 50 percent) in pregnant women [9], women receiving an oral contraceptive [10], postmenopausal women receiving estrogen therapy [11], and patients with estrogen-secreting tumors. Transdermal estrogen has less of an effect than estrogen taken orally. Serum TBG concentrations are increased slightly (10 to 25 percent) in women receiving tamoxifen [12] and raloxifene [13]. (See "Drug interactions with thyroid hormones", section on 'Drugs that influence thyroid hormone binding in serum'.)

•Hepatitis – Patients with acute or subacute hepatitis, even those with minimal elevations in serum aminotransferase concentrations, have increased serum TBG concentrations [14,15].

•Drugs – Several drugs raise serum TBG concentrations, including fluorouracil [16], perphenazine, clofibrate [17], heroin, and methadone [18].

•Acute intermittent porphyria – Acute intermittent porphyria may be associated with increased serum TBG concentrations, via an uncertain mechanism [19,20].

●Evaluation for TBG excess – Obtain a T3 uptake test with calculation of the free T4 index (if available) or measure TBG directly.

The T3 uptake test was designed primarily to detect TBG excess [21]. It measures the number of unoccupied T4-binding sites in serum. It is performed by incubating the patient's serum with labeled T3 and subsequently adding a resin (or other binder such as talc or dextran-coated charcoal) to bind any labeled T3 not bound to serum proteins (figure 1). In states of TBG excess, more labeled T3 binds to TBG and less to the resin, resulting in a low T3 uptake (figure 2). (See "Laboratory assessment of thyroid function", section on 'Serum free T4 and T3'.)

The thyroid hormone-binding ratio (THBR) or index (THBI) is the ratio of the patient's T3 uptake value to the mean of the values in normal subjects. The value in normal subjects is usually normalized to 1 (range 0.83 to 1.16). The THBR (or THBI) is used to calculate the free T4 index [21]. The serum free T4 index, which has no units, is calculated by multiplying the serum total T4 value by the THBR or THBI:

Thus, the changes in thyroid tests with TBG excess can be summarized as follows: high serum total T4, low T3 uptake or THBR/THBI, normal serum free T4 index. In a pregnant woman, for example, the serum total T4 concentration might be 14 mcg/dL (180 nmol/L), but the THBR might be 0.68. The serum free T4 index would be normal (9.5 [14 x 0.68]).

At extremes of TBG excess, the serum free T4 index may not be normal. However, the correct diagnosis can be established by demonstrating that the patient has a normal serum TSH concentration. In addition, serum TBG can be measured directly by radioimmunoassay.

Familial dysalbuminemic hyperthyroxinemia — Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by gain-of-function mutations in the albumin gene (ALB), increasing its affinity for T4, but not T3 [6,22]. As a genetic disorder, it most often occurs in patients of Hispanic ethnicity, with a prevalence of approximately 0.2 percent [5,23].

●Thyroid test findings – Patients with familial dysalbuminemic hyperthyroxinemia have a normal TSH and a high serum total T4 concentration. Free T4 and free T4 index are spuriously elevated [24]. Total T3 is not elevated.

Most free T4 assays are adversely affected by changes in albumin concentration and give spuriously high values [25,26]. The increased binding of T4 in FDH also results in a misleading T3 uptake because the labeled T3 does not bind to the abnormal albumin but does bind normally to the resin and to other serum proteins (figure 3). The net effect is a high serum total T4 concentration and a normal THBR/THBI, so that the calculated serum free T4 index is high. Before sensitive serum TSH assays were available, these patients were commonly misdiagnosed as having hyperthyroidism and treated accordingly.

●Evaluation for FDH – There is usually no need to pursue the diagnosis of FDH if the patient is clearly euthyroid and has a normal serum TSH concentration. However, the diagnosis can be established by any of the following:

•Performing a T4 uptake test using labeled T4 rather than labeled T3 [22]. Serum from patients with FDH binds more labeled T4 than does serum from normal individuals, thereby documenting that serum T4 binding is increased [27].

•Electrophoresis of binding proteins in the presence of labeled T4.

•Measuring serum T4 and free T4 index in the patient's relatives. The inheritance of FDH is autosomal dominant, and therefore, the presence of a similar pattern of laboratory abnormalities in family members is consistent with FDH.

•Assessing gene variants in the ALB gene. R218H, R218P, R222I, and R218S variants have been described [28-30].

The clinical presentation of the R218P variant differed from the patients described above; serum T4 concentrations were 11- to 17-fold above the upper limit of normal (versus two- to threefold), and serum T3 concentrations were elevated up to twofold above the upper limit of normal in some family members [31,32]. This variant may also bind excess cortisol [33].

Abnormal TTR binding of T4 — This very rare disorder is due to production of an abnormal transthyretin (TTR) that, like the abnormal albumin in patients with FDH, binds T4 but not T3 [5,34]. Thyroid tests show normal TSH, mildly elevated total T4, and normal free T4 by equilibrium dialysis [6]. It can be diagnosed by electrophoresis or by using anti-TTR antibodies to immunoprecipitate the protein in the presence of labeled T4 [35]. This condition is important to recognize because it may be associated with TTR amyloidosis, a rare, multisystem disorder causing heart failure and peripheral neuropathy [36].

Anti-T4 immunoglobulins — The presence of anti-T4 immunoglobulins, a rare finding, can cause spuriously high serum total T4 concentrations when T4 is measured by radioimmunoassay [37,38]. These immunoglobulins are antibodies that bind T4, but are distinct from antithyroglobulin (and antithyroid peroxidase) antibodies. Nonetheless, virtually all patients with these antibodies have autoimmune thyroid disease. Most patients have been euthyroid because enough serum T4 was unbound to maintain normal function at the tissue level.

These human anti-T4 antibodies cause spuriously high serum total T4 values in T4 radioimmunoassays because they bind labeled T4, thereby competing with binding of labeled T4 to the rabbit anti-T4 antibodies used in the assays, which then interferes with the competition between labeled and endogenous T4 binding (figure 4). On the other hand, the THBR/THBI (and calculated free T4 index) is normal because most endogenous anti-T4 antibodies do not bind T3. Some, but not all, direct free T4 assays give spuriously high results in the presence of anti-T4 antibodies [39].

Anti-T4 antibodies can be detected by adding labeled T4 to the patient's serum and precipitating the immunoglobulin fraction by the addition of polyethylene glycol [35]. Precipitation of labeled T4 indicates the presence of anti-T4 immunoglobulins.

Anti-T3 immunoglobulins have also been described [37].

Reduced thyroxine deiodination — Several drugs inhibit extrathyroidal T4 deiodination to T3, including amiodarone, propranolol in high doses (eg, >140 mg daily), and the iodinated radiographic contrast agents ipodate and iopanoic acid [40-43] (see "Amiodarone and thyroid dysfunction"). Administration of these drugs may result in hyperthyroxinemia (elevated total and free T4) with normal serum TSH concentrations. Total T3 is generally in the lower end of the normal reference range.

Other conditions — Several other disorders can also cause euthyroid hyperthyroxinemia with a normal TSH:

●Acute psychosis, acting via an uncertain mechanism [44,45] (see "Thyroid function in nonthyroidal illness"). From 1 to 10 percent of patients hospitalized for acute psychosis have modestly elevated serum T4 concentrations [45]. The elevation is usually transient, but measurement of serum TSH is indicated because a few of these patients are actually hyperthyroid [45]. Still, among 12 acutely depressed patients, none had a low serum TSH concentration and seven had slightly elevated concentrations that were probably transient [46].

●High altitude and amphetamines, presumably mediated by a central nervous system mechanism [47,48].

●Symptomatic hyponatremia may be associated with small increases in serum total T4 concentrations [49].

●Some forms of thyroid hormone resistance result in high serum total T4, free T4, and total T3 concentrations with a normal or slightly high serum TSH. These patients may be euthyroid, or have clinical manifestations of hypothyroidism or even hyperthyroidism, because the receptor defect can vary in different organs. (See "Resistance to thyroid hormone and other defects in thyroid hormone action", section on 'Resistance to thyroid hormone beta (RTH-beta and nonTR-RTH)'.)

EUTHYROID HYPERTRIIODOTHYRONINEMIA — 

A variant of albumin with 40-fold increased affinity for T3 but only 1.5-fold increased affinity for T4 has been described in a Thai family: familial dysalbuminemic hypertriiodothyroninemia [50].

In one study, 12.4 percent (13 of 105) newly diagnosed multiple myeloma patients, mostly of the immunoglobulin G (IgG) type, had hypertriiodothyroninemia that resolved with anti-myeloma therapy [51].

EUTHYROID HYPOTHYROXINEMIA

Diagnosis — Euthyroid hypothyroxinemia is a biochemical diagnosis. It should be suspected in patients with a normal TSH, a low serum total T4, and no signs or symptoms of thyroid dysfunction. If not previously obtained, measure free T4.

●If the free T4 is normal, the diagnosis is confirmed, and there is no need to measure any other thyroid tests.

●If the free T4 is low, measure one of the following:

•Free T4 by equilibrium dialysis/tandem mass spectrometry (LC-MS/MS). If normal, the patient is most likely euthyroid.

•T3 uptake with calculated free T4 index (if laboratory testing is available). If normal, the patient is most likely euthyroid. This older method of assessing free T4 was designed to assess abnormal T4 levels in patients with abnormalities in serum thyroxine-binding globulin (TBG). (See 'TBG deficiency' below.)

In confusing cases, measure TBG directly, or obtain a thyroxine binding panel, which measures serum albumin, TBG, and transthyretin (TTR) concentrations as well as T4 binding to each protein.

Determining the etiology — Several conditions can cause euthyroid hypothyroxinemia (table 2). The cause may be obvious from the patient's history (particularly medications and family history).

Binding protein abnormalities

TBG deficiency — Patients with euthyroid hypothyroxinemia due to thyroxine-binding globulin (TBG) deficiency have normal TSH, low total T4, and normal free T4 index. Free T4 should also be normal, but the results are assay dependent.

●Major causes – TBG deficiency occurs in the following settings:

•Hereditary – Hereditary TBG deficiency is an X-linked recessive disorder [5,52,53]. The underlying cause is a mutation in one of the first four exons of the TBG gene [54]. In one family, however, low serum TBG concentrations were autosomally transmitted by an unknown mechanism; the patients' TBG gene was normal [55].

•Hormonal abnormalities – Androgens (high doses) reduce serum TBG concentrations and can result in a reduction in T4 requirement in hypothyroid patients [56]. Other hormonal causes of low serum TBG concentrations include glucocorticoid administration [57], Cushing syndrome, and acromegaly [58].

•Nephrotic syndrome – Urinary loss of TBG in patients with the nephrotic syndrome can result in hypothyroxinemia. Most of the patients are euthyroid, but hypothyroidism can occur in those with poor thyroid reserve or in hypothyroid patients taking T4 (levothyroxine) [59]. (See "Endocrine dysfunction in the nephrotic syndrome", section on 'Thyroid function'.)

•Drugs – L-asparaginase [60], danazol [61], glucocorticoids, and niacin [62] all lower serum TBG concentrations, presumably by decreasing TBG production. (See "Drug interactions with thyroid hormones", section on 'Drugs that influence thyroid hormone binding in serum'.)

Starvation and poor nutrition can cause reductions in both serum TBG and albumin concentrations. (See "Thyroid function in nonthyroidal illness".)

●Evaluation for TBG deficiency – Obtain a T3 uptake test with calculation of the free T4 index (if available) or measure TBG directly.

The T3 uptake test was designed in part to detect abnormalities in serum TBG [21]. This test measures the number of unoccupied T4 binding sites in serum. In states of TBG deficiency, little labeled T3 binds to TBG and most binds to a resin or dextran-coated charcoal. The net effect is that the THBR/THBI is high, leading to a normal serum free T4 index even though the serum total T4 concentration is low (figure 5).

Thus, the changes in thyroid tests with TBG deficiency can be summarized as follows: low serum total T4, high T3 uptake or THBR/THBI, normal serum free T4 index.

At extremes of TBG excess or deficiency, the serum free T4 index may not be normal. However, the correct diagnosis can be established by demonstrating that the patient has a normal serum TSH concentration. In addition, serum TBG can be measured directly by radioimmunoassay.

Decreased T4 binding to TBG — Several drugs, including salicylates [63], salsalate [64], high doses of furosemide (especially in patients with kidney failure) [65], and some nonsteroidal antiinflammatory drugs (fenclofenac and mefenamic acid), inhibit the binding of T4 to TBG. As a result, serum total T4 concentrations fall, but serum free T4 concentrations are normal.

Heparin can result in spuriously low serum total T4 concentrations. It does so by activating lipoprotein lipase in vitro, thereby generating free fatty acids that inhibit T4 binding to albumin [66]. In patients with very high free fatty acids, free T4 by equilibrium dialysis may be spuriously increased (primarily an in vitro artifact) [24,67,68]. These same findings may occur in vivo in heparin-treated patients with severe nonthyroidal illness who have low serum albumin concentrations, which bind free fatty acids. (See "Drug interactions with thyroid hormones", section on 'Drugs that influence thyroid hormone binding in serum'.)

Antiseizure medications — In euthyroid patients, both phenytoin and carbamazepine increase nondeiodinative metabolism of T4 and T3 and displace the hormones from binding proteins. As a result, serum total and free T4 concentrations decrease by approximately 40 percent; the decrease in serum T3 is smaller, but TSH concentrations remain within the normal range [69,70]. The decrease in free T4 is an artifact in most free T4 assays. Serum free T4 is usually measured in diluted serum, and dilution of the antiseizure medication in vitro diminishes its ability to displace T4 from binding proteins. As a result, some of the free T4 becomes bound during the assay, lowering the measured value [71]. Serum free T4 (and T3) concentrations are normal when measured in undiluted serum by ultrafiltration or by equilibrium dialysis [71]. Although less well studied, oxcarbazepine has also been reported to reduce total and free thyroid hormone concentrations [72].

Thus, the thyroid status in patients treated with phenytoin or carbamazepine who have normal pituitary function should be assessed by measuring serum TSH alone. Hypothyroid patients treated with T4 may need an increase in dose after phenytoin or carbamazepine treatment is initiated [73].

Oral T3 administration — T3 is not routinely recommended for thyroid hormone treatment in hypothyroidism (see "Treatment of primary hypothyroidism in adults", section on 'Is there a role for combination T4 and T3 therapy?'). It is, however, used by endocrinologists to treat patients with treated hypothyroidism and persistent symptoms despite a normal TSH and by psychiatrists as adjunctive therapy in patients with depression who respond poorly to tricyclic antidepressant drug therapy [74]. Exogenous T3 suppresses pituitary TSH production and therefore thyroidal T4 synthesis and secretion. Thus, these patients have low total serum T4, normal or slightly elevated T3, and normal or low serum TSH concentrations.

SUMMARY AND RECOMMENDATIONS

●Definitions – Euthyroid hyperthyroxinemia and hypothyroxinemia are characterized by increases or decreases, respectively, in serum total thyroxine (T4), normal thyroid-stimulating hormone (TSH) concentrations, and no symptoms or signs of thyroid dysfunction. Depending upon the etiology, triiodothyronine (T3) concentrations may be increased, reduced, or normal.

Recognition of euthyroid hyper- and hypothyroxinemia is important to prevent unnecessary treatment of patients. However, since most clinicians measure serum TSH as a screening test for thyroid function, and most laboratories now use automated "direct" free T4 assays when needed, a normal serum TSH value is usually not followed by measurement of a total serum T4. Euthyroid hyper- and hypothyroxinemia frequently remain undetected, with no harm to the patient. (See 'Definitions' above.)

●Euthyroid hyperthyroxinemia

•Diagnosis – Euthyroid hyperthyroxinemia is a biochemical diagnosis. It should be suspected in patients with a normal TSH, an elevated serum total T4, and no signs or symptoms of thyroid dysfunction. (See 'Euthyroid hyperthyroxinemia' above.)

If not previously obtained, measure free T4. (See 'Diagnosis' above.)

If the free T4 is normal, the diagnosis is confirmed. There is no need to measure any other thyroid tests and no need for treatment.

If the free T4 is elevated, measure one of the following:

-Free T4 by equilibrium dialysis/tandem mass spectrometry (LC-MS/MS). If normal, the patient is most likely euthyroid.

-T3 uptake with calculated free T4 index (if laboratory testing is available). If normal, the patient is most likely euthyroid. (See 'TBG excess' above.)

In confusing cases, measure TBG directly, or obtain a thyroxine binding panel, which measures serum albumin, TBG, and transthyretin (TTR) concentrations as well as T4 binding to each protein.

•Determining the etiology – Several conditions can cause euthyroid hyperthyroxinemia (table 1). The cause may be obvious from the patient's history (particularly medications and family history). (See 'Determining the etiology' above.)

●Euthyroid hypothyroxinemia

•Diagnosis – Euthyroid hypothyroxinemia is a biochemical diagnosis. It should be suspected in patients with a normal TSH, a low serum total T4, and no signs or symptoms of thyroid dysfunction. (See 'Euthyroid hypothyroxinemia' above.)

If not previously obtained, measure free T4. (See 'Diagnosis' above.)

If the free T4 is normal, the diagnosis is confirmed, and there is no need to treat or to measure any other thyroid tests.

If the free T4 is low, measure one of the following:

-Free T4 by equilibrium dialysis/tandem mass spectrometry (LC-MS/MS). If normal, the patient is most likely euthyroid.

-T3 uptake with calculated free T4 index (if laboratory testing is available). If normal, the patient is most likely euthyroid. (See 'TBG deficiency' above.)

In confusing cases, measure TBG directly, or obtain a thyroxine binding panel, which measures serum albumin, TBG, and TTR concentrations as well as T4 binding to each protein.

•Determining the etiology – Several conditions can cause euthyroid hypothyroxinemia (table 2). The cause may be obvious from the patient's history (particularly medications and family history). (See 'Determining the etiology' above.)